Somatic Mutation in Cerebral Cavernous Malformations

脑海绵状血管瘤的体细胞突变

• 批准号: 7530988
• 负责人: JUDITH Morse GAULT
• 金额: $ 20.21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530988
• 关键词: Abnormal Cell; Accounting; Address; Age; Blood; Blood Vessels; Brain; Brain hemorrhage; CCM1 gene; Cause of Death; Cavernous Malformation; Cell Line; Cells; Cerebrum; Clinical; Collection; Cystic kidney; DNA; Data; Disease; Dissection; Endothelial Cells; Epilepsy; Family; Formalin; Freezing; Future; Genes; Genetic Heterogeneity; Genotype; Germ-Line Mutation; Hemorrhage; Hereditary Disease; Heterogeneity; Individual; Investigation; Knock-out; Lasers; Lead; Lesion; Localized; Maps; Methods; Microscopic; Morus; Mutation; Mutation Analysis; Mutation Detection; Online Mendelian Inheritance In Man; Paraffin Embedding; Pathogenesis; Patients; Phenotype; Polycystic Kidney Diseases; Population; Proteins; Public Health; RNA; Rate; Reporting; Research; Research Personnel; Role; Sampling; Screening procedure; Sequence Analysis; Single-Stranded Conformational Polymorphism; Somatic Mutation; Spinal; Stroke; Symptoms; Technology; Testing; Tissue Sample; Tissues; United States; Vascular Endothelial Cell; base; brain tissue; cell type; disability; improved; innovation; lifetime risk; novel; success

DESCRIPTION (provided by applicant): Cerebral cavernous malformations (CCMs) occur in brain and spinal vasculature. Described as appearing like mulberries in blood vessels, they are found in 0.5% of the population and may cause hemorrhagic stroke and epilepsy. A "two-hit" mechanism has been proposed as a primary mechanism of CCM formation but has been difficult to prove. Consistent with a "two-hit" mechanism, patients with the sporadic nonheritable form of CCM generally have a single CCM; whereas, patients with a heritable form usually have multiple CCMs. A "two-hit" mechanism means that mutations knock-out both copies of a CCM gene in a cell that goes on to form the CCM lesion. Mutations in three genes, CCM1, CCM2 and CCM3 have been identified in heritable forms of CCM. If the "two-hit" mechanism was true, individuals with a germline mutation in a CCM gene would also have a somatic mutation specific to the CCM lesion. Likewise, patients with a sporadic form of CCM would have two somatic mutations in a cell type that makes up the CCM lesion. Several investigations failed to find somatic mutations in CCM lesions. However, the methods used were likely not sensitive enough. In addition only one of three CCM genes was screened. We have identified somatic and heritable germline mutations in two CCM lesions that map to the endothelial cells lining the caverns. Improved methods investigating the endothelial cells of the lesion will be employed. One aim with two projects is proposed to test the hypothesis that somatic mutations in the CCM1, CCM2 and CCM3 genes contribute to lesion genesis. The first project is to collect fresh frozen CCM lesions and characterize them into genetically distinguishable groups (sporadic non- heritable, heritable with known CCM1, 2 or 3 germline mutation and heritable without detectable germline mutation groups). The second project is to screen for CCM1, 2 and 3 somatic mutations in samples from sporadic cases and cases with known germline mutations. The proposed research is fundamental to understanding CCM pathogenesis. PUBLIC HEALTH RELEVANCE: Somatic mutations have been described as a major cryptic mechanism of common diseases because technologies that detect somatic mutations need to be developed. This proposal will develop new methods of somatic mutation detection and provide evidence of somatic mutation involvement in a common genetic disease, cerebral cavernous malformations, that predisposes to stroke and epilepsy.

描述（由申请人提供）：脑海绵状血管瘤（CCM）发生在大脑和脊髓脉管系统中。据描述，它们在血管中看起来像桑葚，存在于 0.5% 的人口中，可能导致出血性中风和癫痫。 “二次打击”机制已被提出作为 CCM 形成的主要机制，但很难证明。与“二次打击”机制一致，散发性非遗传性 CCM 患者通常有单一 CCM；而具有遗传性的患者通常患有多个 CCM。 “双重打击”机制意味着突变会敲除细胞中 CCM 基因的两个副本，从而形成 CCM 病变。已在可遗传形式的 CCM 中发现了 CCM1、CCM2 和 CCM3 三个基因的突变。如果“两次打击”机制成立，那么 CCM 基因中具有种系突变的个体也将具有 CCM 病变特有的体细胞突变。同样，散发性 CCM 患者在构成 CCM 病变的细胞类型中会有两种体细胞突变。多项研究未能发现 CCM 病变中的体细胞突变。然而，所使用的方法可能不够灵敏。此外，仅筛选了三个 CCM 基因之一。我们在两个 CCM 病变中发现了体细胞和可遗传的种系突变，这些突变映射到洞穴内的内皮细胞。将采用改进的方法来研究病变的内皮细胞。提出两个项目的一个目标是检验 CCM1、CCM2 和 CCM3 基因的体细胞突变导致病变发生的假设。第一个项目是收集新鲜冷冻的 CCM 病变，并将其分为可遗传区分的组（散发性非遗传性组、具有已知 CCM1、2 或 3 种系突变的遗传性组以及无法检测到种系突变的遗传性组）。第二个项目是在散发病例和已知种系突变病例的样本中筛查 CCM1、2 和 3 体细胞突变。拟议的研究对于了解 CCM 发病机制至关重要。公共卫生相关性：体细胞突变被描述为常见疾病的主要神秘机制，因为需要开发检测体细胞突变的技术。该提案将开发体细胞突变检测的新方法，并提供体细胞突变参与常见遗传病——脑海绵状血管瘤——易导致中风和癫痫——的证据。